This continuing renewal application for Years 9-13 builds upon our previous studies of the neuroendocrine control of reproduction in the human female, the overall goals of which have been to extend our understanding of (a) the physiology of GnRH secretion in the normal menstrual cycle; (b) the pathophysiology of reproductive axis in the human female. We now propose to examine the neuroendocrine control of the midcycle gonadotropin surge during its spontaneous appearance in normal women with intact hypothalamic-pituitary axes, during estradiol and progesterone evocation of gonadotropin surges in normal subjects, and in GnRH deficient women whose regimen of exogenous GnRH administration can be experimentally varied to actively test hypotheses derived from the monitoring studies. We also propose to examine the neuroendocrine control of the luteal- follicular transition in GnRH deficient women. Specifically, we wish to isolate the contribution of the abrupt increases in frequency of endogenous GnRH secretion we previously described during this transition from waning gonadal feedback to the relatively isolated rises in FSH secretion occurring during this stage of the cycle. Finally, we plan to continue development of new techniques with which to examine reproductive physiology in the human, including: (a) the monitoring of pulsatile secretion of the free alpha subunit of gonadotropins as an alternative marker for endogenous GnRH secretion; (b) specific assays for measurement and determination of the normal physiology of the large molecular weight precursor forms of the alpha-subunit of inhibin and their role in premature ovarian failure. These studies aim to provide direct translation of the most basic new findings in Reproductive Endocrinology to the clinical arena. Focusing as they do upon human investigation, they are detailed and labor intensive in their execution, and possess certain limitations inherent in human research. However, a direct and swift application of advances from the laboratory and lower animal species to the human condition cannot occur without such detailed efforts.